PROTEIN FOLDING

Proteins are made up of folded polypeptide chains, which are composed of 20 different amino acids, each with different chemical properties, that are linked to each other via covalent peptide bonds. The sequence of atoms repeating to form the peptide bonds is called the polypeptide backbone. The side chain of each amino acid, which is the part that makes it different from the other 19 amino acids, can be either polar or nonpolar. The polypeptide chain can fold in many different ways, called “conformations”. Conformations are the spatial arrangement of atoms that can result from movement of atoms without breaking of bonds.
Protein structure can be described in terms of four levels of organization – primary, secondary, tertiary, and quaternary structure. The primary structure is simply the amino acid sequence of the polypeptide chain, and it is important to remember that this sequence contains all the information necessary for the higher orders of structure. The secondary structure is formed by hydrogen-bond interactions of adjacent amino acids. Large numbers of such local interactions form α-helices and β-pleated sheets. The tertiary structure is a more compact, 3-dimensional shape. Large proteins often consist of several protein domains, which are distinct structural units that fold somewhat independently from one another. Quaternary structure is found in those proteins that have 2 or more interacting polypeptide chains, which are then termed subunits.
Let’s examine these four levels of organization in more detail. The primary structure is determined by covalent bonds holding amino acids in a specific order. However, higher orders of structure are primarily dictated by non-covalent forces – ionic bonds, hydrogen bonds, van de Waals, and hydrophobic interactions. The combined strength of large numbers of noncovalent bonds in a protein’s folding pattern determines the stability of any given conformation. The final conformation of a protein is specified by its amino acid sequence and is typically the one that minimizes its free energy.
Secondary structures include α-helices and β-sheets. An α-helix occurs where a polypeptide chain coils like a spring, with one turn every 3.6 amino acids. In α-helices, the N-H of a peptide bond is hydrogen bonded to the C=O of another peptide bond which is one coil up in the helix structure. Note also that all the N-H groups point in one direction – towards the N-terminus - and all the C=O groups point in the opposite direction – towards the C-terminus – and this is what gives the polypeptide chain polarity. The C-terminus is partially positively-charged, while the N-terminus is partially negatively-charged.
β-sheets can form parallel chains, which are made from neighbouring chains running in the same direction, or antiparallel chains, which are made from a polypeptide chain that folds back and forth on itself so that nearby sections run in opposite directions. While hydrogen bonds in an α-helix are intrastrand, hydrogen bonds in β-sheets are interstrand.
Tertiary structure formation can be nucleated by the pattern of polar and nonpolar amino acids in a polypeptide chain, which plays a central role in determining the protein’s final conformation . This is because hydrophobic molecules, such as the nonpolar side chains of certain amino acids, are entropically driven together in an aqueous environment. This limits their disruption of the hydrogen bonding of surrounding water molecules. As a result, nonpolar amino acids tend to be found predominantly in the interior of proteins. Meanwhile, polar amino acids face the outside of the protein, forming hydrogen bonds with one another and the water molecules around the protein. Those polar amino acids that are on the inside of the protein bond with one another or with the polypeptide backbone.
It is thought that protein folding happens roughly along the following lines. Secondary structures form first. Hydrophobic collapse, during which non-polar amino acids aggregate, happens next. Long-range interactions between secondary structures cause further folding to occur. Throughout this process, there may be one or more intermediate states, such as what has been termed a “molten globule”.
As a final note, there are three basic classes of proteins, which are distinguished based on shape and solubility – globular, fibrous, and membrane proteins. Globular proteins are spherical in shape, with as little surface area per volume as possible. These proteins are marginally stable, and this marginal stability facilitates motion, which in turn enables function. Hydrophilic amino acids occupy this small surface area, making these proteins highly soluble in water. Fibrous amino acids are simple, linear structures which have structural roles and are insoluble. Lastly, membrane proteins are associated with cell membranes.

Cell Membrane model from https://www.turbosquid.com/3d-models/...